1. Field of the Invention
This invention relates to 16-membered macrolide anti-infective agents and methods for making and using them.
2. Description of Related Art
Both 14- and 16-membered macrolide antibiotics have been used extensively in human and veterinary medicine. These compounds bind to bacterial ribosomes and inhibit protein synthesis. Erythromycin A, the prototype 14-membered macrolide antibiotic, has a limited activity spectrum and unpleasant gastrointestinal side effects due to an acid catalyzed rearrangement resulting in the creation of derivatives that have high affinity for the motilin receptor. These issues have prompted a large effort in the design of semisynthetic analogs of erythromycin A, leading to compounds such as clarithromycin (Biaxin™), azithromycin (Zithromax™), and the more recently developed ketolides, telithromycin (Ketek™) and cethromycin (ABT773).
In addition to the efforts in the 14-membered macrolide area, there have been considerable efforts in the 16-membered macrolide area. Illustrative disclosures relating to semi-synthetic 16-membered macrolide antibiotics include: Theriault, U.S. Pat. No. 3,784,447 (1974); Gorman et al., U.S. Pat. No. 3,459,853 (1969); Lukacs et al., U.S. Pat. No. 4,918,058 (1990); Narandja et al., U.S. Pat. No. 5,023,240 (1991); Maring et al., U.S. Pat. No. 5,140,014 (1992); Hecker et al., U.S. Pat. No. 5,545,624 (1996); Jaynes, U.S. Pat. No. 5,677,287 (1997); Narandja et al., U.S. Pat. No. 5,688,924 (1997); Narandja et al., U.S. Pat. No. 5,922,684 (1999); Or et al., U.S. Pat. No. 6,680,299 B2 (2004); Katz et al., US 2002/0128213 A1 (2002); Ma et al., US 2004/0014687 A1 (2004); Hamao et al., EP 0,070,170 A1 (1983); Narandja et al., EP 0,287,082 (1988); Lopotar et al., EP 0,410,433 A2 (1991); Narandja et al., EP 0,985,679 A1 (2000); Hamao et al., JP 62-221695 A (1987); Tanaka et al., J. Antibiot. 35 (1), 113-116 (1982); Sakamoto et al., J. Antibiot. 37 (12), 1628-1634 (1984); Debono et al., J. Antibiot. 42 (8), 1253-1267 (1989); Ruggeri et al., J. Antibiot. 42 (9), 1443-1445 (1989); Maring et al., J. Antibiot. 44 (4), 448-450 (1991); Grandjean et al., J. Carbohydrate Chem., 15 (7), 831-855 (1996); and Narandja et al., J. Antibiot. 52 (1), 68-70 (1999); the disclosures of which are incorporated herein by reference.
Due to the continuing emergence of antibiotic-resistant bacterial strains, there exists an ongoing need for new antibacterial compounds. We have discovered new 16-member macrolide antibacterial compounds having a useful spectrum of activity against various bacteria.